Skin homeostasis is achieved through precisely controlled epidermal growth and differentiation, which are regulated by an integrated signaling network. Elucidation of how the pathways within the network coordinate with each other to maintain the balance between proliferation and differentiation will contribute to our knowledge of skin physiology and pathology. The retinoid-related orphan receptor ROR1 is a critical factor in differentiation and development of several tissues, and it is also involved in calcium signaling and circadian rhythm. Our preliminary findings indicate that ROR1 expression is induced with differentiation in primary human keratinocytes (HKCs) and is absent in squamous cell carcinoma (SCC). Increased ROR1 expression is sufficient to induce expression of keratinocyte differentiation markers, while suppression of ROR1 has the opposite effect. Moreover, there are several ROR1 binding elements present in the promoter region of Notch1 gene, which is a direct determinant of keratinocyte entry into differentiation, and increased ROR1 expression could modulate Notch1 transcription and Notch activity. We therefore hypothesize that ROR1 plays a key role in control of epidermal differentiation through an interconnection with Notch signaling. To test this hypothesis, we will first examine the impact of increased and reduced ROR1 expression on proliferation and differentiation of human primary keratinocytes (HKCs). In parallel, we will perform histological and biochemical analysis of skin derived from ROR1 null mice to more conclusively establish the role of ROR1 in epidermal proliferation and differentiation control. These studies will be followed by a mechanistic characterization of the reciprocal modulation between ROR1 and the Notch signaling pathway. The results from this study will provide fundamental insight into skin biology and may have direct bearing on developing new treatment for various skin diseases.